Full Text DE-95-004

HEALTH EFFECTS OF DENTAL AMALGAMS IN CHILDREN

NIH GUIDE, Volume 24, Number 11, March 24, 1995

RFA:  DE-95-004

P.T. 34

Keywords: 
  Dentistry 
  Biomaterials 
  Toxicology 


National Institute of Dental Research

Letter of Intent Receipt Date:  May 22, 1995
Applications Receipt Date:  August 24, 1995

PURPOSE

The National Institute of Dental Research (NIDR) invites applications
for cooperative agreements for a multidisciplinary clinical trial
addressing the health effects of dental amalgams in children.  Public
concerns about the safety of dental amalgam fillings containing
mercury continues despite assurances from the public health
community.  The general purpose of the trial is to investigate the
possible relationship between lowdose exposure to mercury vapor from
dental amalgam restorations and the occurrence of specific health
conditions in children.  To accomplish this the NIDR is interested in
supporting a prospective, randomized clinical trial involving
children from high risk caries populations needing restorative dental
treatment with dental amalgam.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Health Effects of Dental Amalgams in
Children, is related to the Priority area of oral health.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock No. 017-001-
00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit, non-profit,
public and private organizations, such as dental or medical schools,
universities and research institutions.  Applications from foreign
institutions are not eligible, however, applications may have
international components.  Applicants from institutions that have a
General Clinical Research Center (GCRC) funded by the NIH National
Center for Research Resources may wish to identify the GCRC as a
resource for conducting the proposed research.  If so, a letter of
agreement from either the GCRC program director or principal
investigator should be included with the application.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this
program will be a cooperative agreement (U01), which is an assistance
mechanism, rather than an acquisition mechanism.  Under the
cooperative agreement, the NIH purpose is to support and/or stimulate
the recipient's activity by collaborating and otherwise working
jointly with the award recipient in a partnership role, but it is not
to assume direction, prime responsibility, or a dominant role in the
activity.  Details of the responsibilities, relationships and
governance of a study funded under a cooperative agreement are
discussed later in this document under the section "Terms and
Conditions of Award."

The cooperative agreement mechanism of support will be used because
substantial NIDR programmatic staff involvement with the awardee is
necessary to facilitate coordination of a multidisciplinary approach
to the research topic, to assist in protocol development,
particularly in the selection of appropriate health endpoints, in
quality control procedures, and to play an active role in monitoring
the safety of study participants.

FUNDS AVAILABLE

This RFA is a one-time solicitation.  At least one application is
expected to be funded as a result of this RFA.  However, in the event
that a multicenter trial is needed to obtain sufficient numbers of
subjects and to provide standardized analysis of biological samples,
additional awards will be made.  In either case, the funds available
for the first year of support for the RFA are expected to total no
more than $500,000.  This level of support is conditional upon the
receipt of applications of high scientific merit.  Awards are
expected to be made in Fiscal Year 1996.  Although the financial and
programmatic plans of the NIDR provide for support beyond the initial
five year award, awards pursuant to this RFA are also contingent upon
the availability of funds.

RESEARCH OBJECTIVES

Background

Dental amalgam, a mixture of approximately equal parts of elemental
mercury and other metals including silver, tin, copper, zinc and
palladium or indium, has been in continuous use as a dental
restorative material for well over a century.  It has been the
material of choice in restoring posterior teeth because of its
strength, durability and relative low cost.  It is estimated that
approximately one-half of the 200 million restorative procedures
performed in 1990 utilized amalgam as the material of choice.

Mercury is widely found in the environment with trace levels present
in air, water, and food.  The toxicity of elemental mercury and its
compounds is widely recognized.  Experimental studies on animals, and
biopsy observations in humans based on occupational exposure to
organic mercury can affect the immune system to produce a nephrotic
syndrome.  Research on animals indicate large strain differences in
susceptibility to the autoimmune response to mercury.  In humans
signs and symptoms associated with mercury intoxication from
elemental mercury include tremor, ataxia, personality change, loss of
memory, insomnia, fatigue, depression, headaches, irritability,
slowed nerve conduction, weight loss, appetite loss, psychological
distress, and gingivitis.

Several review articles have indicated that few large scale human
studies have been conducted investigating the potential adverse
effects of dental amalgams.  One large study of Swedish women was
reported in which none of the correlations between number of amalgam
fillings and clinical symptoms or complaints were found to be
positive.   Most of the signs and symptoms of mercury toxicity have
been associated with longterm occupational exposure to air
concentrations of mercury greater than 50 fg/m3, reflected by urinary
mercury concentrations greater than 100 ng/ml.  While clinically
significant effects have not been reported below air concentrations
of 100 fg/m3, preclinical manifestations consisting of short term
memory loss and slowed peripheral nerve conduction have been reported
below this level.  No clinical findings on impairment of kidney
function have been found in persons exposed to airborne
concentrations of mercury below 100 fg/m3.

Purported public concerns over the release of mercury from dental
amalgam fillings have been recurring for many years.  However, recent
concerns have intensified with the discovery that small amounts of
mercury vapor may be released from amalgam restorations and
eventually absorbed into body tissues.  Although, with the exception
of allergic or hypersensitive reactions in a small number of
patients, no adverse health effects have been demonstrated following
the placement of dental amalgam fillings in humans.  Nevertheless,
there is a concern over the margin of safety between known toxic
levels of mercury, regardless of source, and those levels in
individuals having numerous amalgam fillings.

A Health Assessment Program sponsored by the American Dental
Association (ADA) was initiated in 1975.  Each year, at the annual
ADA meeting, practicing dentists volunteer to participate in this
screening program. Questionnaires are given to all volunteers and
urinary samples are collected for mercury assays.  Between 1975 and
1983 over 9400 dentists participated in this program.  Urine
specimens were collected from 4272 of these dentists, 3793 of whom
were general dentists.  Their average urinary mercury concentration
was 14.2 ng/ml, 4.8% had concentration levels over 50 ng/ml, 1.3
percent levels over 100 ng/ml.  A subsequent report of the findings
for 19851986 showed a decrease in urinary mercury concentration,
averaging 5.8 ng/ml and 7.6 ng/ml.  Although some five percent to
seven percent of these professionals had high urinary mercury
concentrations (over 20 ng/ml) no abnormal glomerular or tubular
kidney dysfunction was reported.

In 1991, the ADA reported results of a survey of 1000 adults which
showed that nearly one-half believed that health problems could
develop from dental amalgam.  In the same year, the National
Institutes of Health (NIH) and the Food and Drug Administration (FDA)
separately convened panels of experts to evaluate the current state
of knowledge regarding amalgam-related hazards.  Both panels of
experts agreed that current research information does not demonstrate
a causal relationship between dental amalgam and a human health
problem.  Subsequent to these meetings the Swedish Medical Research
Council held a scientific conference in 1992 on the biological
consequences of mercury released from dental amalgam and reported
that it does not, according to available data, contribute to systemic
disease, toxicological or teratological effects.

In contrast, a symposium on the toxicity of mercury vapor from dental
amalgam, held in 1992 under the auspices of the Society of
Toxicology, reported that more remains to be learned about the
effects of chronic, low level mercury exposure associated with dental
amalgams.  Attendees called for more research in the areas of
neurologic, reproductive, developmental and renal effects, and the
mechanisms that underlie them.

The need for additional research was echoed by the Public Health
Service when in 1991, at the direction of the Assistant Secretary for
Health, it brought together subject matter experts as well as
specialists in risk and benefits assessment on the Committee to
Coordinate Environmental Health and Related Programs (CCERHP) to
reach an independent judgment about the degree of health risk, if
any, posed by the use of dental amalgam as a restorative material.
These experts determined that current research did not demonstrate a
health hazard for the vast majority of individuals exposed to mercury
vapor at levels commonly encountered.  In a 1993 report from CCERHP,
the Assistant Secretary for Health, reaffirmed the position
enunciated earlier by PHS that there are no data to compel a change
in the current use of dental amalgam.  Nevertheless, given the
available scientific evidence, the possible adverse health effects
resulting from the use of dental amalgam cannot be fully discounted.
The strongest evidence documenting any potential hazards of amalgam
restorations would be obtained from prospective cohort clinical
studies, especially a clinical trial involving an amalgam restorative
material in children.  In particular, given the current state of
knowledge, information is needed to try to define more precisely the
human dose response relationship of low dose mercury exposure from
dental amalgam restorative materials.

Children in the mixed dentition stage have been selected as the
subjects of choice because of the importance of establishing a
baseline in a group with little or no exposure to mercury.  Further,
the NIDR is interested in studying a population that experiences
caries at a high rate, who have received little or no restorative
treatment prior to entry into the prospective trial, and in which
there is a high likelihood of need for amalgam restorations.
Finally, a childhood population of this age group will allow at least
seven years, and hopefully more, of followup, a period that should
prove sufficient to detect even the most subtle effects, if any, of
amalgam.

Objectives and Scope

The aims of this clinical trial are to investigate the following:

1.  Potential neurological, psychological/behavioral, renal,
endocrine or other relevant organ system impairments or dysfunctions
in children that are attributable to exposure to amalgam
restorations;

2.  Degree to which Hg concentrations in urine, blood or other
relevant tissues differ in children with and without exposure to
amalgam restorations; and

3.  Progression of Hg concentrations in urine, blood or other
relevant tissues over time in children beginning with the time of the
initial placement of amalgam restorations.

It is anticipated that the clinical trial would be performed in
populations at high risk for dental caries consisting of individuals
that have received little or no previous treatment and which are in
need of restorative treatment.  Such populations may come from within
the U.S., outside of the U.S., or a combination of the two.  It is
anticipated that routine restorations of carious teeth supplemented
by an aggressive caries prevention and education program consistent
with appropriate standard of care would be instituted for the study
population throughout the study period.

Due to the nature of the trial, a multidisciplinary approach
including the appropriate mix of experts from epidemiology,
biostatistics, neurology, behavioral sciences/child psychology,
toxicology, and other relevant specialties is believed to be
essential to its success.  To accomplish the objectives within the
multidisciplinary context, substantive NIDR scientific input is
viewed as essential during both the developmental and operational
phases of the project.  Consensus is necessary regarding specific
neurological, psychological/behavioral, and/or other appropriate
health endpoints as well as for the length of time, estimated to be
in the range of five to seven years, for study subject followup
during which even the most subtle psychological or physiological
changes could be detected.

SPECIAL REQUIREMENTS

The organizational structure of the study may take one of several
forms depending on the ability to recruit sufficient numbers of
subjects, to perform analyses on biological samples, and to perform
data entry and analysis.  These functions may all be able to be
performed at one institution or with subcontracts to individual
centers under a single award.  On the other hand, it may be necessary
to fund multiple sites with individual awards.  In the latter case,
it may also be necessary to fund a coordinating center to insure
efficient conduct of the trial. In the event that multiple sites are
required to carry out the trial, it is imperative that principal
investigators of the individual centers agree to follow a single
clinical protocol as well as to make measurements in a uniform and
prescribed manner.

Specific rationale should accompany the suggested outcome measures
recommended as primary response variables.  The variables selected
should be specific enough to pertain to mercury vapor exposure.  If
multiple primary outcome measures are recommended, the methodology
for combining results should be addressed to avoid confusion
regarding procedures used for interpreting statistically significant
findings (i.e., explain how positives will be validated).

The importance of identifying and documenting the availability of an
adequate population of subjects for this trial cannot be
overemphasized.  The assumptions made in the calculation of sample
size determination must be made explicit with supportive
documentation provided whenever possible.  Procedures for soliciting
diverse subpopulations will be required as will specific procedures
for monitoring and managing the trial, including any quality control
procedures.  If more than one country or cultural/ethnic group is
involved, a detailed description of precautions that will be taken to
ensure that all instruments used will be valid across the various
subgroups is necessary.

Administrative responsibility needs to be documented in detail
including responsibility for recruitment and enrollment, eligibility
requirements, and criteria for determining whether a field center
qualifies for inclusion in the study.

Special attention must be given to the potential attrition problem
during the study period, indicating the methods that will be used to
encourage subjects to remain in the study, the techniques used for
monitoring dropout rates at individual study sites, and the possible
corrective actions that will be employed.

The method of providing restorative care for all participants at the
conclusion of the study must be specified.  Appropriate level of
dental care will have to be provided to all participants requiring
restorative care as a result of participating in this study or
coincident to participating in the study.

Terms and Conditions of Award

These special Terms of Award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR parts 74 and 92, and other HHS,
PHS, and NIH Grant Administration policy statements.

The administrative and funding instrument used to undertake the
project is a cooperative agreement (U01), an "assistance" mechanism
(rather than an "acquisition" mechanism) in which substantial NIH
scientific and/or programmatic involvement with the awardee is
anticipated during the performance of the activity.  Under the
cooperative agreement, the NIH purpose is to support and/or stimulate
the recipient in a partner role, but it is not to assume direction,
prime responsibility or a dominant role in the activity.  Consistent
with this concept, the dominant role and prime responsibility for the
activity resides with the awardee(s) for the project as a whole,
although specific tasks and activities in carrying out the studies
will be shared among the awardees and the NIDR Project Scientist who
is the Assistant Director for Program Development, Extramural
Program.

Awardees will have the usual responsibilities of award recipients,
including protocol development, participant recruitment and followup,
data collection, quality control, interim data and safety monitoring,
final data analysis and interpretation, and preparation of
publications, as well as responsibilities for collaboration with
other awardees, as appropriate, and collaboration with the NIDR
Project Scientist.

Awardees will have lead responsibilities for the project as a whole
and it is anticipated that the awardees will have lead
responsibilities in all joint tasks and activities, except it is
anticipated that the NIDR Project Scientist(s) will have lead
responsibilities in quality control and catalyzing interim monitoring
of data and safety and may, consistent with publication policy to be
adopted by the Steering Committee as well as NIH publication policy,
have lead responsibilities in the preparation of some publications.
Awardees will retain custody of and have primary rights to the data
developed under these awards, subject to Federal government rights of
access consistent with current HHS, PHS, and NIH policies.

In addition to the NIDR Project Scientist, a representative from the
Epidemiology and Oral Disease Prevention Program (EODPP) will have
responsibilities in protocol development, quality control, interim
data and safety monitoring, final data analysis and interpretation,
preparation of publications, collaboration with awardees, and project
coordination.

The main governing body of the study will be the Steering Committee.
The Committee will have primary responsibility for developing common
protocols, facilitating the conduct and monitoring of studies, and
reporting the study results.  The composition of the Committee will
depend on the final organization of the trial.  For a multicenter
trial, the Committee will be composed of the principal investigator,
representatives from each of the recruitment centers, a
representative of the coordinating center, representatives from each
of the analytic centers, the NIDR Project Scientist and a
representative of the EODPP.  For a single center trial, the
Committee will consist of the PI, representatives from any analytic
centers, the NIDR Project Scientists and a representative of the
EODPP.  Each member of the Committee will  have one vote except for
representatives from the NIDR who, together, shall have only one
vote.  The Chairperson, who will be someone other than an NIDR staff
member, will be selected by the Committee. Subcommittees will be
established by the Steering Committee, as it deems appropriate.

The collaborative protocol will be developed by the Steering
Committee and followed by all awardees.  This protocol may be
reviewed by an external committee convened by NIDR.  The protocol
will be implemented only with the concurrence of the awardee(s) and
NIDR.  Data will be submitted centrally to the Coordinating Center.
The protocol will define rules regarding access to data and
publications.  An independent Data and Safety Monitoring Board
(DSMB), to be appointed by NIDR, will review progress at least
annually and report to NIDR.  The DSMB will examine data for any
untoward effects of the treatment procedure or of Hg amalgam on
subjects as well as for statistically significant increases in Hg
between baseline and subsequent measurements.  The DSMB will have the
responsibility of reporting to the NIDR the occurrence of untoward
effects of Hg amalgam, any human subject ethical issues, or if
statistical significance is reached in one of the major study
endpoints before the planned end of the trial.

The NIDR reserves the right to terminate or curtail the study (or an
individual award in the event of (a) failure to develop or implement
a mutually agreeable collaborative protocol, (b) substantial
shortfall in participant recruitment, follow up, data reporting,
quality control, or other major breach of the protocol, (c) reaching
a major study endpoint substantially before schedule with persuasive
statistical significance, or (d) human subject ethical issues.

Any disagreement that may arise in scientific/programmatic matters
within the scope of the award, between award recipients and the NIDR
may be brought to arbitration.  An arbitration panel will be composed
of three members one selected by the Steering Committee (with the
NIDR members not voting) or by the individual awardee in the event of
an individual disagreement, a second member selected by the NIDR, and
the third member selected by the two prior members.  This special
arbitration procedure in no way affects the awardee's right to appeal
an adverse action that is otherwise appealable in accordance with the
PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45
CFR part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This  new policy results
from the NIH Revitalization Act of 1993 (Section 492 of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators may obtain copies from these sources or from program
staff or contact the person listed under INQUIRIES.  Program staff
may also provide additional relevant information concerning the
policy.

LETTERS OF INTENT

Prospective applicants are asked to submit, by May 22, 1995, a letter
of intent that includes a descriptive title of the proposed
center(s), the name, address and telephone number of the center
director(s), the identities of other key personnel and the number and
title of this RFA.  Although a letter of intent is not required, is
not binding, and does not enter into the review of subsequent
applications.  It allows NIDR staff to estimate the potential review
workload and to avoid possible conflict of interest in the review.

The letter of intent is to be addressed to Dr. Norman S. Braveman at
the address listed under INQUIRIES.

APPLICATION PROCEDURES

Prospective applicants are advised to communicate with program and
grants management staff of the NIDR as early as possible in the
planning phase of application preparation.  NIDR staff are available
to assist applicants to ensure that the objectives, structure, and
the budget format for the proposed study are acceptable.

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for this cooperative agreement.  These forms are
available at most institutional offices of sponsored research; from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, 5333 Westbard Avenue, Room 449,
Bethesda, MD 20892, telephone 301/435-0714; and from the program
administrator listed under INQUIRIES.

The RFA label available in the form PHS 398 must be affixed to the
bottom of the face page of the original application.  Failure to use
this label could result in delayed processing of the application such
that it may not reach the review committee in time for review.  In
addition, the RFA title and number must be typed in item 2a of the
face page of the application form and the YES box checked.

The instructions accompanying form PHS 398 must be followed to the
extent possible, but some modification will be necessary.  For
example, a new Table of Contents must be prepared giving page numbers
for all items in the application.  Pagination must be consecutive
throughout the application.  A consolidated budget for the complete
project for the entire project period must be presented (see page 5,
form PHS 398).  Separate detailed, annual and total budgets for the
entire project period for each center must be presented (use pages 4
and 5, form PHS 398).  Direct and indirect costs are to be given.
Funds may be requested for professional, technical, and
administrative personnel; consultant services; equipment; supplies;
travel; patient costs directly related to the research; minor
renovations and other costs.  Detailed justification of the budget
requests will be required.

Under Research Plan, describe the goals of the center(s) and discuss
the background and significance of the topics being addressed.
Explain how the proposed research will accomplish the objectives.
Describe the organizational and administrative structure, the
responsibilities of the principal investigator and other
investigators, and the proposed mechanisms for monitoring scientific
progress.  Address issues raised under the "Special Requirements" and
"Terms and Conditions" sections of the RFA.

An abstract (page 2, form PHS 398) must be completed for the entire
application.

Submit a signed, original of the application, including the
Checklist, and three signed, exact photocopies, in one package to:

Division of Research Grants
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express or courier service)

At the time of submission, two additional copies also must be sent
to:

Dr. H. George Hausch
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN-44F
45 Center Drive MSC 6402
Bethesda, MD  20892-6402

Applications must be received by August 24, 1995.  If an application
is received after that date, it will be returned to the applicant.

REVIEW CONSIDERATIONS

General Considerations

All applications will be judged on the basis of the scientific merit
of the proposed protocols and the documented ability of the PI and
the research team to conduct the essential study components as
broadly outlined in the RESEARCH OBJECTIVES of the RFA.  Although
technical merit of the application is important, it will not be the
sole criterion for selection.  Other considerations such as
importance and timeliness of the proposed trial, access to patients,
and multidisciplinary nature of the studies will be part of the
evaluation criteria.

Review Method

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Applications that are incomplete or
nonresponsive to this RFA, or exceed the first year budget limit of
$500,000 in direct costs, including any indirect costs associated
with consortium arrangements, will be returned to the applicant
without further consideration.  Waivers of the receipt date deadline
and budget limitation will not be granted.  Those applications that
are complete and responsive will be evaluated in accordance with the
criteria stated below for scientific and technical merit by a special
review committee convened by the NIDR Scientific Review Office.

As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and assigned
a priority score.  Applications judged to be noncompetitive will be
withdrawn from further consideration and the Principal Investigator
and the official signing for the applicant organization will be
notified.

Review Criteria

Applicants are encouraged to submit and describe their own ideas on
how best to meet the goals and objectives of the RFA.  They are
expected to address issues identified under SPECIAL REQUIREMENTS of
the RFA.  Applications will be judged primarily on the scientific
quality of the application, the appropriateness, importance and
timeliness of the proposed approach, adequacy of facilities, access
to patients, the multidisciplinary nature of the study, the approach
to cost containment, the discussion of considerations relevant to the
RFA, the expertise of the investigators, their capability to perform
the proposed research, and a demonstrated ability to work as part of
a multidisciplinary team as well as with the NIDR project scientists.

The review group will assess the scientific merit of the protocols
and related major factors, including:

1.  The rationale for and prioritization of the primary health
outcome variables proposed for the trial.

2.  The appropriateness of the study design regarding length of
study, composition and size of study groups, anticipated number of
centers needed, inclusion of appropriate control group(s), and entry
criteria of subjects required at participating centers.

3.  Documentation (e.g., pilot study results) relative to the
feasibility of the study population proposed for use in the trial,
including susceptibility to dental caries, need for restorative
treatment, lack of previous exposure to amalgam fillings or exposure
to mercury from other environmental or dietary sources.

4.  The adequacy of the identified study population, including the
potential for enrollment, participation by females and minorities as
study subjects, participant access for the duration of the trial
period, and stability of participants for the duration of the study.
Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.

5.  The scientific and administrative qualifications, experience and
commitment of the identified investigators to conduct this study.
The adequacy of the proposed interdisciplinary team to conduct this
trial.  The expertise and experience of the data management team
identified by the applicant, including the quality control procedures
suggested for data entry, editing, storage and processing procedures.
The quality and thoroughness of the analytical plan suggested in the
study protocol.

6.  The extent to which the investigators have anticipated potential
problems; the loss of a senior investigator, change of an
administrative head at a study site controlling access to a large
group of study participants, difficulties in recruiting participants,
corrective actions for clinics experiencing difficulty during the
study period.

7.  The technical expertise, demonstrated experience and capabilities
of the laboratory to perform the mercury assays at the sensitivity
level required for this study. The technical merit and justification
for other core resources requested and the appropriateness of the
budget for each component.

8.  The thoroughness and adequacy of quality control procedures for
accuracy and reliability of the clinical and laboratory data,
monitoring the adherence to the study protocol by all investigators,
and safety of procedures used.

9.  The strategy for conducting longterm followup of the study
participants should this be desired later including provisions for
treatment of exiting participants from the study, during or at its
conclusion, including providing for any restorative treatment needs.

AWARD CRITERIA

The NIDR appreciates the value of complementary funding from other
public and private sources, including foundations and industrial
concerns, for activities that will complement and expand those
supported by the NIDR.  Such support is encouraged to supplement
funding for this trial.

Applications recommended for funding by the National Advisory
Research Dental Council will be considered for award based upon: (a)
scientific and technical merit as determined by peer review,
importance of the proposed clinical trial, timeliness,
multidisciplinary nature of the study, and the requirements
explicitly stated in the RFA; (b) in the case of a multicenter trial,
compatibility of the various elements to make a successful
collaborative program a reasonable likelihood; and (c) availability
of funds.

Letter of Intent Receipt Date:  May 22, 1995
Application Receipt Date:       August 24, 1995
NARDC Review:                   January 1996
Anticipated Award Date:         March 1996

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding scientific program issues to:

Norman S. Braveman, Ph.D.
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN 24B
45 Center Drive MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-2089
FAX:  (301) 480-8318
Email:  BravemanN@de45.nidr.nih.gov

Direct inquiries concerning fiscal policy matters to:

Ms. Theresa Ringler
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AS-55
45 Center Drive  MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.121.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Parts 74 and 92. [Part 92 applies when state and local
governments are eligible to apply as "domestic organization."].  This
program is not subject to the intergovernmental review requirements
of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routing education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the phs
mission to protect and advance the physical and mental health of the
american people.

.

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